The human p53 transcription factor induces cell cycle arrest and apoptosis in response to DNA damage1 and cellular stress,2 thereby playing a critical role in protecting cells from malignant transformation. The E3 ubiquitin ligase HDM2 controls p53 levels through a direct binding interaction that neutralizes p53 transactivation activity, exports nuclear p53, and targets it for degradation via the ubiquitylation-proteasomal pathway.3, 4 Loss of p53 activity, either by deletion, mutation, or HDM2 overexpression, is the most common defect in human cancer.5 Tumors with preserved expression of wild type p53 are rendered vulnerable by pharmacologic approaches that stabilize native p53. In this context, HDM2 targeting has emerged as a validated approach to restore p53 activity and resensitize cancer cells to apoptosis in vitro and in vivo.6 HDMX (HDM4) has also been identified as a regulator of p53. Moreover, studies have shown a similarity between the p53 binding interface of HDM2 and that of HDMX.6a 
The p53-HDM2 protein interaction is mediated by the 15-residue α-helical transactivation domain of p53, which inserts into a hydrophobic cleft on the surface of HDM2.7 Three residues within this domain (F19, W23, and L26) are essential for HDM2-binding.8, 9 